treatment of african children with severe malaria - towards evidence-informed clinical practice...

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Treatment of African children with severe malaria -towards evidence-informed clinical practice usingGRADENyokabi Musila1*, Newton Opiyo1 and Mike English1,2

Abstract

Background: Severe malaria is a major contributor of deaths in African children up to five years of age. Onevaluable tool to support health workers in the management of diseases is clinical practice guidelines (CPGs)developed using robust methods. A critical assessment of the World Health Organization (WHO) and Kenyanpaediatric malaria treatment guidelines with quinine was undertaken, with a focus on the quality of the evidenceand transparency of the shift from evidence to recommendations.

Methods: Systematic reviews of the literature were conducted using the Grading of RecommendationsAssessment, Development and Evaluation (GRADE) tool to appraise included studies. The findings were used toevaluate the WHO and Kenyan recommendations for the management of severe childhood malaria.

Results: The WHO 2010 malaria guidance on severe malaria in children, which informed the Kenyan guidelines,only evaluated the evidence on one topic on paediatric care using the GRADE tool. Using the GRADE tool, thiswork explicitly demonstrated that despite the established use of quinine in the management of paediatric cases ofsevere malaria for decades, low or very low quality evidence of important outcomes, but not critical outcomessuch as mortality, have informed national and international guidance on the paediatric quinine dosing, route ofadministration and adverse effects.

Conclusions: Despite the foreseeable shift to artesunate as the primary drug for treatment of severe childhoodmalaria, the findings reported here reflect that the particulars of quinine therapeutics for the management ofsevere malaria in African children have historically been a neglected research priority. This work supports theapplication of the GRADE tool to make transparent recommendations and to inform advocacy efforts for a greaterresearch focus in priority areas in paediatric care in Africa and other low-income settings.

BackgroundSevere falciparum malaria is a medical emergency. Anestimated 800,000 annual deaths occur in African coun-tries South of the Sahara as a direct result of malaria inchildren aged five years and less [1]. The Roll Back MalariaPartnership’s goal is to control and ultimately eliminatemalaria, which is consistent with the Millennium Develop-ment Goals (MDGs) 4, to reduce under-five child mortal-ity, and 6 to reduce the incidence of infectious diseasesincluding malaria. However, until achieved, appropriatetreatment of severe malaria to prevent fatality and

disability will be required. In spite of its narrow therapeu-tic window, which dictates careful dosing and monitoring,quinine has been the drug of choice for the treatment ofsevere malaria in Africa for over 30 years (and before thatwas in use since the 17th century). Exciting new resultsfrom an African multi-centre trial now suggest that artesu-nate should replace quinine as the first-line treatment [2].In Kenya, however, changes are anticipated to take placeprogressively over the coming years as practical issues,such as making changes to national policy, procurementand supply chain issues and re-training of health workers,are tackled. In particular, the latter will demand a signifi-cant injection of funds from the national malaria controlprogramme (Personal Communication, Dr Elizabeth Juma,Head of Division of Malaria Control, Ministry of Public

* Correspondence: [email protected] and Newborn Health Group, Kenya Medical Research Institute-Wellcome Trust Research Programme, PO Box 43640 - 00100, Nairobi, KenyaFull list of author information is available at the end of the article

Musila et al. Malaria Journal 2011, 10:201http://www.malariajournal.com/content/10/1/201

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Health and Sanitation). Meanwhile, quinine will inevitablyremain the default treatment.Best approaches to treatment are often encompassed in

clinical practice guidelines (CPGs), tools to support healthworkers to make evidence-informed decisions in the man-agement of their patients. Ideally CPGs combine the bestavailable research gathered using standardized, robust,systematic methods and contextual factors, such as cost,feasibility, values, resources [3]. The World Health Organi-zation (WHO), which is tasked with producing global clin-ical guidance, particularly for developing countries, hasrecently adopted one such transparent and systematicapproach to developing its CPGs. This process applies theGrading of Recommendations Assessment, Developmentand Evaluation (GRADE) tool to transparently assess thequality of research evidence and develop recommenda-tions [4]. The GRADE approach has rapidly becomewidely used in full or in part, and is endorsed or used byorganizations including WHO, the UK’s National Institutefor Health and Clinical Excellence (NICE), the ScottishIntercollegiate Guidelines Network (SIGN), and theCochrane Collaboration [5].In March 2010, the WHO revised its malaria treatment

guidance as a framework for country-level policy makersto adapt. For the first time, it incorporated the GRADEapproach [6]. In Kenya, the Division of Malaria Control(DoMC) took the opportunity to revise its national guide-lines for treatment of severe malaria in children, makingthem consistent with the 2010 WHO Malaria treatmentguidelines (Table 1). In so doing, it changed Kenya’srecommended quinine regimen from one that had beendisseminated and promoted for over 10 years. Specificchanges were an increase in the loading dose and mainte-nance doses of quinine. This policy change coincided withefforts by researchers, the Kenyan Ministry of Medical Ser-vices and others to update CPGs for management of 12key paediatric conditions, including malaria [7], anapproach also attempting to employ the GRADE tool [8].However, as the 2010 WHO guidance did not employ theGRADE approach to systematically appraise the evidenceavailable to inform the optimum use of quinine in Africanchildren, a series of systematic reviews were conducted toexamine the quality of evidence available to help guide use

of quinine in this population using the GRADE approach.This work demonstrates how treatment of severe malariahas largely been neglected by the research community.Further, it demonstrates how the GRADE tool helps makethis explicit, pointing to its potential value for highlightingfailures to invest in research on neglected diseases orpopulations.

MethodsKey clinical questions to be tackled in a series of systema-tic reviews that addressed the themes of effectiveness andsafety of quinine for the treatment of Kenyan childrenwith severe malaria were identified. These were:1) Systematic review 1: Is there a value in administra-

tion of a loading dose of quinine in African childrenwith severe malaria?2) Systematic review 2: Should Kenya change its recom-

mendation for treatment of severe malaria in childrenunder 5 of 15 mg/kg loading dose followed by 10 mg/kgevery 12 hours and replace it with the WHO recom-mended regimen of 20 mg/kg loading dose followed by10 mg/kg every 8 hours?3) Systematic review 3: What are the pharmacoki-

netics and effectiveness of IV-administered quininecompared to IM-administered quinine in African chil-dren with severe malaria?4) Systematic review 4: Is there a link between IV-

administered quinine and risk of hypoglycaemia in Afri-can children with severe malaria?The clinical questions were developed in a PICO (Popu-

lation, Intervention, Control/Comparator, Outcome) for-mat and literature searches conducted in PubMed and theCochrane Library (up to September 2010) using MeSH(Medical Subject Headings) search terms derived fromPubMed. Free text searches with no language or time lim-itations were conducted. Additional searches were alsoconducted in PubMed using the clinical queries filter tool.Furthermore, bibliographies in the WHO guidelines andabstracts of the 5th Multilateral Initiative on Malaria Pan-African Malaria Conference (2-6 November 2009, Nairobi,Kenya) were scanned. In a first round, identified manu-script titles were independently screened by two investiga-tors (NM, ME) using pre-defined inclusion/exclusion

Table 1 Summary of World Health Organization (2010) and Government of Kenya (2005 and 2010) clinical practiceguidelines for the management of children with severe malaria

Treatment for children aged <5 years with a diagnosis ofsevere malaria

GoK 2005Basic Paediatric Protocols*

GoK 2010 Malaria CaseManagement Guidelines

WHO 2010 Malaria CaseManagement Guidelines

Pre-referral quinine loading dose 15 mg/kg IM injection 20 mg/kg IM injection 20 mg/kg IM injection

First-line treatment with quininedose

15 mg/kg loading dose then 10 mg/kg every 12 hours by IV infusion ordivided IM injection

20 mg/kg loading dose then 10 mg/kg every 8 hours by IV infusion ordivided IM injection

20 mg/kg loading dose then10 mg/kg every 8 hours byIV infusion ordivided IM injection

*Based on 1998 DoMC Malaria Treatment Guidelines.


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criteria (Table 2). In a second round of screening, abstractsand full texts were read to select relevant studies to beincluded in the systematic reviews. Data from includedstudies were extracted into an in-house data extractiontool. Quinine doses were uniformly presented in the saltform as quinine sulphate. The GRADE tool was then usedto critically appraise the quality of each study and follow-ing that, the quality of all available evidence informing aparticular question/outcome combination was categorizedbased on GRADE guidelines (Table 3). Where no evidenceof heterogeneity was found, binary outcome data frommultiple studies were pooled in a random-effects modelusing STATA 11 (STATA Corporation, College Station,Texas, USA), and assessed for heterogeneity using the I-Squared test.

ResultsThe number of studies identified in the literature searchfor each question and then the number screened foreligibility and final included studies in the respectivesystematic reviews are presented in a series of flow dia-grams (see Additional File 1).

Systematic review 1: Is there a value in administration ofa loading dose of quinine in African children with severemalaria?One Cochrane systematic review that was a meta-analysisof four African randomized controlled trials was identi-fied [9] (Table 4). Moderate to low quality evidence forcritical and important outcomes indicates that a quinineloading dose of 19 to 21 mg/kg may make little or no dif-ference to mortality, coma recovery time, convulsion fre-quency, asexual parasitaemia at 24 and 48 hours,neurological sequelae or adverse events including hypo-gylcaemia, hypotension and arrhythmia. However, mod-erate quality evidence indicates that a loading dose of 20

mg/kg quinine may reduce fever clearance time[Weighted Mean Difference (WMD) 11.11, 95% Confi-dence Interval (CI) 20.04 to 2.18; n = 68] and parasiteclearance time (WMD 7.44, 95% CI 13.24 to 1.64; n = 67)as well as cause temporary hearing loss [Risk Ratio (RR)3.14, 95% CI 1.05 to 9.38; n = 33] (see Additional File 2).

Systematic review 2: Should Kenya change itsrecommendation for treatment of severe malaria inchildren under 5 of 15 mg/kg loading dose followed by10 mg/kg every 12 hours and replace it with the WHOrecommended regimen of 20 mg/kg loading dosefollowed by 10 mg/kg every 8 hours?There were no head to head comparisons or suitable indir-ect comparison studies identified in the literature search.

Systematic review 3: What are the pharmacokinetics andeffectiveness of IV-administered quinine compared to IM-administered quinine in African children with severemalaria?Seven studies in African children that evaluated quinineadministered with a loading dose by the IV or IM routewere identified [10-16]. In addition, three studies identi-fied by a Cochrane review but on African children notstrictly having severe malaria were included [17]. Thesestudies compared the effectiveness of quinine adminis-tered with a loading dose by the rectal (IR) and the IVroute [18,19] and the IR and the IM route [20] (Table 5).

Systematic review 3a: What is the effectiveness of IV-administered quinine compared to IM-administeredquinine in African children with severe malaria?Two studies were identified that assessed the compara-tive effectiveness of quinine route of administration bythe IV and IM route when a loading dose of 20 mg/kgwas administered, with a maintenance dose of either 10

Table 2 Study selection inclusion/exclusion criteria

Inclusion criteria Exclusion criteria

P. falciparum malaria Uncomplicated malaria

Randomized Controlled Trials (observational studies to be considered if no RCT evidence) IR administration

Children < 5 years old (older children and adult data to be considered if no studies in children)

Diagnosis of severe or complicated malaria, confirmed with microscopy or rapid diagnostic test or cerebral malaria

African setting

IM or IV administration

Table 3 Evidence quality and level of confidence in estimates using the GRADE approach

Evidence Quality Level of confidence in estimate

High Further research is very unlikely to change our confidence in the estimate of effect

Moderate Further research is likely to change our confidence in the estimate of effect, and may change the estimate

Low Further research is very likely to change the estimate of effect, and is likely to change the estimate

Very low The estimate of effect is very uncertain

Adapted from Guyatt et al 2008 [26]


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mg/kg every 12 hours [11] or 10 mg/kg every 8 hours[13]. There was no difference between treatment groupsin all the reported outcomes of the individual studiesthat were all appraised as low quality evidence - risk ofdeath, incidence of neurological sequelae, number ofconvulsions, coma resolution time, parasite clearancetime, fever clearance time, number of hypoglycaemicepisodes or haemoglobin levels (see Additional File 3).Further indirect evidence on mortality from 3 studies,deemed to provide very low quality evidence (see Addi-tional File 3), suggested there was no associationbetween risk of death (or any other outcome) and routeof administration from the studies that investigated IRquinine vs IV quinine (n = 91 patients) in African chil-dren [Odds Ratio (OR) 0.50, 95% CI 0.20 to 1.26; n =

186] [18,19] (Figure 1) or in one study that investigatedIR vs IM quinine (OR 0.15, 95% CI 0.01 to 3.28; n = 58)[20]. Overall, therefore, available evidence is low or verylow quality to guide decisions on route of quinineadministration with the possibility that clinically impor-tant risks or benefits exist, but are not recognized.

Systematic review 3b: What is the pharmacokinetics ofIV-administered quinine compared to IM-administeredquinine in African children with severe malaria?Four identified studies evaluated the pharmacokineticsof quinine when administered at a loading dose of 20mg/kg, followed by a maintenance dose of 10 mg/kgevery 12 hours [10-12,16]. One study evaluated thepharmacokinetics of quinine when administered at a

Table 4 Characteristics of studies that evaluated quinine loading dose (Systematic review 1)

Test quinine sulphate dose (IV) Comparator quinine sulphate dose (IV)

Study Age range Country Loading dose Maintenance dose Uniform dose

Assimadi 2002* (N = 72) 8 months to 15 years Benin 21 mg/kg 10.5 mg/kg every 12 hours 15.9 mg/kg every 12 hours

Fargier 1991* (N = 20) 15 years and above Cameroon 19 mg/kg 9.7 mg/kg every 8 hours 9.7 mg/kg every 8 hours

Pasvol 1991# (N = 59) up to 12 years Kenya 20 mg/kg 10 mg/kg every 12 hours 5 to 10 mg/kg every 12 hours

Tombe 1992 (N = 33) 14 years and above Kenya 20 mg/kg 10 mg/kg every 8 hours 10 mg/kg every 8 hours

*Reported quinine doses converted from quinine base to quinine salt using salt conversion factor of 1.21#N = 20 patients who received IM quinine were excluded from this analysis

Adapted from Lesi et al 2004 Cochrane systematic review [9]

Table 5 Characteristics of studies that evaluated effectiveness and pharmacokinetics of quinine by route ofadministration (IV vs IM or indirect comparison of IR vs IV and IM vs IR) (Systematic review 3)

Study ID Age range Country IV Quinine Dose IM Quinine Dose

Waller 1990 (N = 21) 19 months to8 years

Gambia N/A 20 mg/kg loading dose, then10 mg/kg every 12 hours

Pasvol 1991‡ (N = 59) up to 12 years Kenya 20 mg/kg loading dose, then 10 mg/kg every12 hours

20 mg/kg loading dose, then10 mg/kg every 12 hours

Krishna 1991 (N = 120) 1 to 10 years Ghana N/A 20 mg/kg loading dose, then10 mg/kg every 12 hours

Schapira 1993 (N = 104) 6 months to7 years

Mozambique 20 mg/kg loading dose, then 10 mg/kg every8 hours


Winstanley 1993 (N = 22) 7 months to6.8 years

Kenya 14 mg/kg loading dose, then 10 mg/kg every12 hours


Winstanley 1994 (N = 9) 1 to 3 years Kenya 15 mg/kg loading dose, then 10 mg/kg every12 hours

N/A

van Hensbroek 1996 (N = 16) 5 to 23months

The Gambia 20 mg/kg loading dose, then 10 mg/kg every12 hours


Study ID Age Country IR Quinine Dose IV Quinine Dose

Achan 2007† (N = 110) 6 months to5 years

Uganda 20 mg/kg base loading dose, then 10 mg/kgevery 8 hours, until oral treatment possible

8 mg/kg base every 8 hours, untiloral treatment possible

Bareness 1998† (N = 77) 2 to 15 years Niger 11.8 mg/kg base loading dose, then 8.8 mg/kgevery 8 hours for 2 days, then oral treatmentwith chloroquine

4.7 mg/kg base every 8 hours for2 days, then oral treatment withchloroquine

Study ID Age range Country IR Quinine Dose IM Quinine Dose

Bareness 2001† (N = 58) 2 to 15 years Niger 17.9 mg/kg base loading dose, then 11.75 mg/kg base every 12 hours

7.5 mg/kg base every 12 hours

† Quinimax formulation which consists of 96% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine‡N = 21 patients who received a lower dose of IV administered 10 mg/kg loading dose then 5 mg/kg every 12 hours were excluded from the IV vs IMeffectiveness analysis only.


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loading dose of 20 mg/kg, followed by a maintenancedose of 10 mg/kg every 8 hours [13]. Very low qualityevidence showed that there was no difference in thereported pharmacokinetic parameters of quinine in theindividual studies - volume of distribution (Vd), maxi-mum circulating concentration (Cmax), half-life (t1/2),area under the curve (AUC) (Table 6).

Systematic review 4: Is there a link between IV-administered quinine and risk of hypoglycaemia inAfrican children with severe malaria?Six studies that evaluated the risk of hypoglycaemia inthe population and setting of interest to this reviewwere identified [2,21-25] (Table 7). Of these, five studies[21-25] found no effect of IV quinine when given at aslow infusion rate on the number of hypoglycaemic epi-sodes or insulin levels in the children. An associationwith hypoglycaemia was observed in children, however,when quinine was administered at a high infusion rate.Overall quality of evidence was rated as low or very lowto inform decisions on alternative quinine regimens.Recently published high quality evidence, which evalu-ated the effectiveness of quinine and the artemisininderivative artesunate in African children up to 15 yearsof age, however, found 2.8% of patients treated with

quinine developed hypoglycaemic episodes, with artesu-nate treatment associated with a significantly lower risk(OR 0.63, 95% CI 0.43 to 0.91; n = 5,425) [2] (see Addi-tional File 4).

DiscussionThe WHO malaria treatment guidelines updated in2010 have introduced the appraisal of studies using theGRADE tool but only for newly acquired evidence sincethe 2006 guidelines. Of relevance to severe malaria, thisencompassed only one topic, the comparison of safetyand effectiveness of quinine and artemisinin derivativesin treating severe malaria, with reviews conductedbefore the recently published large trial on artesunate[2]. Other topics in the WHO 2010 guidance of (i) load-ing dose of quinine (20 mg/kg) vs. no loading dose, (ii)effectiveness of IM vs IM quinine, (iii) IM artemether vsIV quinine and (iv) safety and efficacy of pre-referraltreatment with IR artesunate were reported as narrativesummaries of the evidence only, with no transparentassessment or grading of recommendations. Althoughthe new data indicating the superiority of artesunatecompared with quinine (see Additional File 5) [2] willchange the landscape for guidelines, many African coun-tries are likely to continue to rely on quinine therapy for

Achan 2007; IR n=56, IV n=54

Barennes 1998; IR n=39, IV n=37

Total: IR n=95, IV n=91Figure 1 Meta analysis of comparison of effect of IR and IV administered quinine on mortality in African children.


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Table 6 Pharmacokinetic parameters of IV and IM administered quinine in African children (Systematic review 3b)

Study ID(sample size)

EvidenceQuality

Route ofadmn

Sample sizeper arm

Quinine loadingdose

Quininemaintenance dose

Infusiontime

Cmax(mg/l)

tmax (h) t1/2 (h) Cl(ml/min/kg)

Vd (l/kg) AUC(mg/l/h)

Pasvol 1991 (N = 43) Low IV n = 21 10 mg/kg 5 mg/kg 2 h 9.7 ± 5.3 2.7 ± 1.3 8.9 ± 4.0 1.36 ± 0.58 0.87 ±0.27

145 ± 61

Winstanley 1993(N = 22)

VeryLow

IV n = 12 14 mg/kg 10 mg/kg bd 2 h 13.8 ±3.1

- 16.4 ±8.8

0.45 ± 0.13 0.45 ±0.10


VeryLow

IV n = 9 15 mg/kg 10 mg/kg bd 2 h 17.9 ±2.9

- 12.6 ±3.1

0.81 ± 0.24 0.75 ±0.11

Pasvol 1991 (N = 43) Low IV n = 18 20 mg/kg 10 mg/kg bd 2 h 15.3 ± 5.5 2.4 ± 1.5 12.5 ± 3.2 1.19 ± 0.29 1.22 ±0.16

254 ± 86

van Hensbroek 1996(N = 16)

VeryLow

IV n = 6 20 mg/kg 10 mg/kg bd 4 h 17.48 ±2.43

- 13.16 ±6.43

0.51 ± 0.16 1.04 ±0.21

354 ± 143

Waller 1990 (N = 21) VeryLow

IM n = 21 20 mg/kg 10 mg/kg bd N/A 15.4 ±4.5

3.23 ±1.63

18.8 ±8.0

0.89 ± 0.81 - 449 ±243

Pasvol 1991 (N = 43) Low IM n = 20 20 mg/kg 10 mg/kg bd N/A 15.3 ±7.6

2.4 ±1.7

15.7 ±8.2

1.12 ± 0.56 1.22 ±0.32

332 ±254


VeryLow


1.6 ±1.7

- - - -

van Hensbroek 1996(N = 16)

VeryLow


1.08 ±0.37

15.31 ±7.16

0.59 ± 0.25 1.32 ±0.49

358 ±164

Krishna 2001(N = 120)

VeryLow

IM n = 120 20 mg/kg 10 mg/kg bd N/A - - 19.9 ±4.4

0.05 - -

Legend:

Cmax (mg/l): Maximum circulating concentration

tmax (h): Time at maximum circulating concentration

t1/2 (h): Half-life

Cl (ml/min/kg): Clearance

Vd (l/kg): Volume of distribution

AUC (mg/l/h): Area under the curve.

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severe malaria in children for some years to come. Qui-nine has well known, serious adverse effects and pre-vious and current WHO recommendations (2010) havenot used systematic approaches when attempting toappraise the evidence to guide dosing.Despite more than 30 years of clinical use, only studies

of important (not critical) outcomes and only very low orlow quality evidence are available to inform most paedia-tric quinine dosing decisions. Thus, there are no datadirectly comparing the Kenyan regimen of the last 12years and only limited data suggesting either the IV or IMroutes may be used, although IM quinine is mainly recom-mended for pre-referral treatment due to the risks ofdeveloping an IM injection abscess and other complica-tions when incorrectly administered (Personal Communi-cation, Dr Elizabeth Juma, Head of Division of MalariaControl, Ministry of Public Health and Sanitation). Verylimited data also suggest that hypoglycaemia is more likelywith faster rates of administration. Only in the case of theuse of a loading dose is there moderate quality evidence toguide recommendations, but only for what was consideredas non-critical outcomes. These included reduced feverand parasite clearance time with loading doses, but also

higher risks of transient hearing loss with higher loadingdoses [9].This work thus indicates, historically, how the Kenyan

policy on quinine dosing that has been promoted nation-wide for over 10 years, with considerable investments indissemination of guidelines and in-service training sup-ported by global funds, was based predominantly on lowor very low quality evidence by today’s standards. Theavailable very low quality evidence does however suggestsimilar pharmacokinetic parameters for the lower doseKenyan regimen as the currently recommended WHOregimen. The fact that the 2010 WHO quinine dosingregimens (that are unchanged) are also based on lowquality evidence, even for safety, does not provide anobvious rationale for Kenya’s change to adopt the WHOguidance. While it is considered entirely appropriate thatother factors are considered in making recommendationsbased on evidence [3,26], this process is rarely transpar-ent, as is the case with Kenya’s change of its quinineregimen.The emergent message from the series of systematic

reviews we conducted is the paucity of high quality evi-dence that may inform the dose, route of administration

Table 7 Characteristics of studies that evaluated risk of hypoglyacemia with IV-infused quinine (Systematic review 4)

Study ID Evidencequality

Agerange

Country IV Quinine Dose and diluent Infusiontime

Infusionrate (ml/kg/24 h)

GlucoseThreshold(mmol/l)

Molyneux1989(N = 29)

Very low 2 to 9years

Malawi 10 mg/kg in 5% glucose in halfstrength Darrow’s solution

1 h 80 < 2.2

10 mg/kg in 5% glucose in halfstrength Darrow’s solution

3 h 80 < 2.2

20 mg/kg in 5% glucose in halfstrength Darrow’s solution

3 h 80 < 2.2

Okitolonda1987(N = 9)*

Very low 6 to 10years

Zaïre 10 mg/kg in 30 ml salinesupplemented with 2.5%glucose every 8 hours

1 h 105 < 2.8

Kawo 1991(N = 97)

Very low Up to 7years

Tanzania 10 mg/kg in 10 ml/kg of 5%glucose every 8 hours

4 h Notreported

< 2.2

Ogetii 2010(N = 1237)

Low Up to12 years

Kenya 15 mg/kg loading dose in 5%dextrose then 10 mg/kg in 5%dextrose every 12 hours

2 h Notreported

< 3, < 2.8and < 2.2

20 mg/kg loading dose in 5%dextrose then 10 mg/kg in 5%dextrose every 8 hours

4 h Notreported

< 3, < 2.8and < 2.2

Taylor 1988(N = 95)

Very low 7monthsto 8years

Malawi 20 mg/kg loading dose then 10mg/kg every 8 hours

Loading dose4 h,thenmaintenancedose 2 to 8 h

80 < 2.2

Dondorp2010

High Up to15 years

Multi-centre trial in Mozambique, TheGambia, Ghana, Kenya, Tanzania,Nigeria, Uganda, Rwanda andDemocratic Republic of Congo

¥20 mg/kg loading dose in 5-10ml/kg of 5% dextrose then 10mg/kg in 5-10 ml/kg of 5%dextrose every 8 hours

Loading dose4 h,thenmaintenancedose 2 to 8 h

Notreported

Notreported

*Data from N = 5 adults were excluded from this analysis

Ogetti 2010 = Retrospective review of case notes. ¥Quinine was administered by the IM and IV route.


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and safety of treatment of African children diagnosedwith severe malaria with quinine, notwithstanding thatquinine has been the standard treatment of severemalaria for decades (Table 8). This contrasts starklywith the evidence available to inform policy for childrenwith non-severe malaria. Here international efforts andfunding have supported over fifty randomized controlledtrials in recent years [27]. Despite huge investments totackle malaria over the last decade or more [28] it isclear therefore that severe malaria in African childrenhas remained a neglected disease. In conducting thesesystematic reviews we found the GRADE approach avery useful tool for making the presence of only lowquality evidence explicit. This paper postulates that thewider use of this or other similar approaches can helpbuild advocacy efforts for a greater research focus onpriority areas in paediatric therapeutics in African andother low-income settings.The recent findings of the large multicentre trial

demonstrating superiority of artesunate over quinine forsevere malaria in African children [2] provide a clearargument for a change in approach on the continent.These data demonstrate how poor the foundationalbasis was for the use of quinine and should help argue

that the practical difficulties of introducing artesunateshould be overcome as soon as possible. Further, thiswork supports that efforts to introduce explicit methodsof examining the evidence base for treatment of childrenin low-income settings should be strongly supported.

Additional material

Additional file 1: Flow diagrams of the study selection process foreach of the systematic review questions. A series of flow diagramsdepicting the number of studies found in the literature search, thenumber excluded during assessment and the final number included inthe systematic reviews.

Additional file 2: GRADE Table for studies included in systematicreview 1: Is there a value in administration of a loading dose ofquinine in African children with severe malaria?. Critical appraisal andoutcome data using the GRADE tool for Lesi 2004 Cochrane systematicreview.

Additional file 3: GRADE Tables for studies included in systematicreview 3a: What is the effectiveness of IV-administered quininecompared to IM-administered quinine in African children withsevere malaria?. Critical appraisal and outcome data using the GRADEtool for Schapira 1993, Pasvol 1991 (direct comparisons) and includedstudies from the Eisenhut 2009 Cochrane systematic review - Achan2007; Barennes 1998; Barennes 2001(indirect comparisons)

Additional file 4: GRADE Table for studies included in systematicreview 4: Is there a link between IV-administered quinine and riskof hypoglycaemia in African children with severe malaria?. Critical

Table 8 Summary of quinine systematic reviews in the treatment of severe malaria in African children andrecommendations for evidence-informed clinical practice

Clinical Issue Recommendation Evidencequality/strengthofrecommendation

Systematic review 1: Is there a value inadministration of a loading dose of quinine inAfrican children with severe malaria?

Quinine loadingdose [9]

Loading dose results in faster clearance of malariaparasites from the blood stream and thus fasterclearance of fever and thus loading dose should beadministered, with monitoring and patient/care giversupport for episodes of partial hearing loss adverseevent

Moderate

Systematic review 3a: What is the effectivenessof IV-administered quinine compared to IM-administered quinine in African children withsevere malaria

Quinine route ofadministration: IVvs IM [11,13,18-20]

The clinical outcome of IV-administered quinine vs.IM-administered quinine is equivocal in thetreatment of African children with severe malaria.However, due to reported side effects with IM route,such as risk of abscess and pain, the IV route ispreferred.

Low to very low

Systematic review 3b: What is thepharmacokinetics of IV-administered quininecompared to IM-administered quinine in Africanchildren with severe malaria

Quinine paediatricdose [10-12,14-16]

Pharmacokinetic profile of the old and new Kenyandosing regimen are similar

Low

Systematic review 4: Is there a link between IV-administered quinine and risk of hypoglycaemiain African children with severe malaria?

Quinine and risk ofhypoglycaemia[2,21-25]

The risk of hypoglycaemia with quinine treatment inAfrican children with severe malaria may becountered by administering the quinine at a lowinfusion rate.Glucose levels should be monitored due tohypoglycaemic risk that occurs due to the diseaseand/or quinine treatment, and should be treatedwith glucose infusion

Low to high

AQUAMAT Findings Quinine vsartemisininderivatives [2]

Artesunate is a superior treatment to quinine forAfrican children with severe malaria and should bestrongly considered for implementation as a first linetreatment, taking contextual factors such as cost-effectiveness into account

High


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appraisal and outcome data using the GRADE tool for Ogetti 2010 andDondorp 2010.

Additional file 5: GRADE Table for the African multi-centre trial(AQUAMAT). Critical appraisal and mortality data using the GRADE toolfor Dondorp 2010 and Eltahir 2010.

AcknowledgementsNM is funded by ME’s Wellcome Trust Senior Fellowship (#076827).NO is funded by a Wellcome Trust Strategic Award (#084538).ME is funded by a Wellcome Trust Senior Fellowship (#076827).NM acknowledges statistical advice from Ms Tansy Edwards and Dr JohnWagai.The authors acknowledge useful discussions with Dr Andrew Nyandigisi andDr Dorothy Naisiae of the Division of Malaria Control, Ministry of PublicHealth & Sanitation. This paper is published with the permission of thedirector of KEMRI.

Author details1Child and Newborn Health Group, Kenya Medical Research Institute-Wellcome Trust Research Programme, PO Box 43640 - 00100, Nairobi, Kenya.2Department of Paediatrics, John Radcliffe Hospital, University of Oxford,Oxford, UK.

Authors’ contributionsME conceived of the topics for the systematic reviews. NM developed themethodology and conducted the reviews with assistance from NO. NMdrafted the manuscript and ME and NO contributed to it. All authors readand approved the final manuscript.

Competing interestsThe authors declare that they have no competing interests.

Received: 18 January 2011 Accepted: 21 July 2011Published: 21 July 2011

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doi:10.1186/1475-2875-10-201Cite this article as: Musila et al.: Treatment of African children withsevere malaria - towards evidence-informed clinical practice using GRADE.Malaria Journal 2011 10:201.


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